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Disclaimer:  This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on literature review at the time of the blog and may change as new evidence evolves.

Rapamycin: Hedging the bet on a long and healthy life

On an expedition to Easter Island in 1964, Canadian scientist Georges Nógrády reached down in a desolate field and collected a soil sample. He was trying to find out why the barefoot inhabitants of the remote island rarely got tetanus. Unknown to Nógrády, there was a molecule lurking within the dirt that would change the entire field of gerontology forever.

Easter Island - Chuck Meakin, Meakin Metabolic Care

Chemists at Ayerst Pharmaceuticals would later isolate a compound to be named rapamycin from Nógrády’s sample. Scientists studying rapamycin would then discover that rapamycin was the most potent anti-aging compound ever found, forever changing the trajectory of aging research and our understanding of aging.


In the decades following the discovery of rapamycin, scientists uncloaked how the molecule impinged on the aging process. Rapamycin's target protein was named the Mammalian Target of Rapamycin, or mTOR for short. Specifically, rapamycin inhibited the activity of mTOR. Under normal conditions, mTOR senses when nutrients like carbohydrates and certain amino acids are present and then instructs the cell to grow, divide, and repair. Conversely, when an animal is calorically restricted, mTOR is inhibited and instructs the cell to undergo autophagy, a complex series of pathways that recycle nutrients for more immediate needs. Autophagy is a cellular cleansing where old, defunct proteins are broken down into constituent amino acids and reassembled into new pristine and functional proteins. Herein lies the magic of rapamycin, a drug that inhibits mTOR and induces autophagy, cleaning out the pathological proteins that constitute aging and thus rebuilding old and clunky cellular organelles into brand-new ones.



Image: Active mTOR inhibits autophagy. Therefore, inhibiting mTOR with rapamycin stimulates autophagy. - Chuck Meakin

Aging researchers look to a governmental program called the Interventional Testing Program (ITP) that selects the most promising anti-aging compounds and tests them with a refreshingly simple endpoint: Does the compound cause mice to live longer or not, and if so, how much? The ITP tests each compound at three separate sites to ensure the effect is reproducible. It is an incredibly well-run program and is considered the gold standard for intervention testing. ITP results.


Across from each compound tested is a link titled "View Survival Analysis," the Kaplan Meier survival curve is generated from the pooled data of each of the three testing sites for male and female mice. The ITP has tested the most promising compounds, including metformin, statins, aspirin, resveratrol, NADH, etc. Rapamycin has consistently shown to be one of the most robust life extensions of all the compounds tested.


Of course, the results of the ITP sparked even more interest in rapamycin for scientists interested in disease prevention and longevity, leading to the obvious question: Will rapamycin have the same health-promoting effect in humans as it has demonstrated in preclinical animal models? As rapamycin gains popularity, examining what is known and what is not is essential to determine if it is right for you.


Where science ends and faith begins


Where Science Ends

A remarkable mouse study led to one of the few human studies done to date. With the ability of rapamycin to extend the lifespan of mice well-established, researchers designed an experiment that asked a more specific question: What is the impact of rapamycin on the immune system, a major hallmark of aging? To test this, the researchers divided mice into two groups: one group of old mice and one of young mice. In the group of young mice, they determined the dose of influenza virus that killed 100% of the mice. Next, they vaccinated young mice against influenza and inoculated them with the same amount of influenza virus that killed 100% of the unvaccinated mice. One hundred percent of the young, vaccinated mice survived the illness; their young, healthy immune systems could mount a robust, post-vaccination, immunological response. They then repeated the experiment with the old mice. Even with vaccination, 30% of the old mice died when challenged with the influenza dose; their old immune systems could not mount a robust response. Finally, the researchers took one more group of aged mice. They gave them rapamycin for six weeks and then repeated the experiment: vaccinating them and then inoculating them with influenza virus. This time, however, 100% of the old, vaccinated mice survived. The six weeks of rapamycin rejuvenated their old immune systems.(1) This remarkable demonstration of the ability of rapamycin to restore aged immune systems in mice inspired another group to study the effect of a compound called a rapalog (a molecule that acts the same as rapamycin but has a slightly different chemical structure) on the immune systems of older people. To do this, they randomized 218 people over the age of 65 into four groups:

  • .5 rapalog daily for six weeks before vaccination

  • 5mg rapalog once a week for six weeks before vaccination

  • 20mg rapalog once a week for six weeks before vaccination

  • Placebo for six weeks before vaccination

After six weeks of treatment with the rapalog, all the subjects received an influenza vaccine. The researchers measured the number of antibodies generated from the vaccine to measure how well the subject's immune systems functioned. The result was consistent and compelling: The three treatment groups developed about 20% more antibodies to the influenza viruses in the vaccine compared to the placebo group. Additionally, the treatment groups displayed a reduction in the cellular marker related to immunosenescence (a general term describing the immune system's diminished functionality with age).(2)


For the researchers studying rapamycin, this study was a milestone – for the first time, it was evidence that rapamycin directly benefited elderly human’s immune response, integral to some of the 12 hallmarks of aging.(4)


Because rapamycin has FDA approval for organ transplant rejection and is historically used at much higher doses and with other immunosuppressive drugs, the side effects and safety profile are known for people taking it continuously for long periods. As such, and especially at low doses for longevity, rapamycin is known to be a safe drug with minimal side effects; the most pronounced is mouth sores. A recent survey of over 300 people taking it for healthy aging found favorable impacts on Covid metrics with less morbidity from the infection, long Covid incidence, and vaccination side effects. The only negative result was a 15% rate of mild aphthous mouth ulcers.(5) This, however, is where the science of rapamycin ends.


Where Faith Begins


The allure of restoring youth transcends time and culture. The fabled fountain of youth that Ponce de León searched for in the 16th century first appeared in the writing of Herodotus in the 5th century BC, then in the 3rd century AD Greek writings, and later in the stories of Prester John from the early Crusades. Rapamycin is the modern manifestation of the ancient, cross-culture yearning to restore the vigor of youth.


Unlike the mythical fountain of youth, the rapamycin tale springs from hard science and empirical data. Rapamycin has extended the lifespan of all species studied to date and has demonstrated the ability to restore the immune systems of elderly humans. What is not known, however, is the ultimate question: What is the effect if a healthy person begins taking rapamycin in adulthood? Will they have a reduced probability of developing cardiovascular disease, cancer, or dementia? Will they have an increased ability to fight off infections like Sars-Cov2 or influenza? Will they live a healthier, longer life? We do not know because the trials that would answer these questions have yet been done.


Even so, respected experts in gerontology are willing to take the leap of faith that it will have a beneficial effect. And that leap is not taken blindly – The research on rapamycin all points in that direction.


However, rapamycin’s specific mechanism of action – the inhibition of mTOR and the induction of autophagy – raises another important question: Does rapamycin offer a benefit over and above the lifestyle modifications known to induce autophagy like fasting and exercise? At this nexus, experts in the field veer in different directions. *


This point is highlighted in a recent podcast with longevity expert Peter Attia, M.D., and Matt Kaeberlein, PhD. who both take rapamycin, and renowned rapamycin and mTOR expert David Sabatini, M.D., Ph.D., who does not take rapamycin.


In the discussion, Attia asked Sabatini to elaborate on why he does not take rapamycin.

Sabatini: It isn’t such a willful thing…I wonder, and you and I have discussed, if you eat OK and exercise, if rapamycin is a memetic of a healthy diet…are you getting that extra benefit? It wouldn’t be that I am afraid of it, I am not, but would it do anything?

Attia: But isn't there a hedging or Pascal’s wager, which is as long as you could convince yourself that it is not harmful, would the worst thing you are doing is wasting a lot of money because it isn't cheap?

Sabatini: So, I agree, so that’s where the laziness factor comes in…(Sabatini had admitted that one of the reasons he does not take rapamycin is that he has not had the motivation to get around to it).


This exchange lies at the heart of where science ends, and faith begins. The most critical remaining question about rapamycin that looms large is whether it offers a benefit over and above lifestyle factors that inhibit mTOR naturally. There are preclinical studies as well that suggest rapamycin additionally impacts in some way all 12 hallmarks of aging beyond just autophagy. Faith is probably the wrong word to use. Science has predictive power, meaning existing data allows scientists to extrapolate the likely outcomes of untested assumptions. However, we will only know the answer to that question with absolute certainty once clinical trials answer it. And this is what anyone considering taking rapamycin needs to know and consider. Rapamycin may or may not offer a benefit over and above lifestyle factors, but some experts are willing to wager that it does. It is a wager worth taking to some, including Dr. Attia and clinical trial rapamycin expert Matt Kaeberlein, PhD., also on the podcast. This wager comes with minimal risk and costs about 10 dollars per week as options to get the non-compounded generic drug verified to be pharmaceutical grade at this new lower cost now is available.


MeakinMeakinCare.com is adding a more affordable tool to our array of options for the Metabolic Optimization Protocol as we measure lifestyle, biometrics, and laboratory values over time in our chronic disease prevention program. Let's start a conversation.


Seven Point Summary:

  1. Rapamycin is a compound found on Easter Island that has been shown to be the most potent anti-aging compound ever found.

  2. Rapamycin inhibits the activity of mTOR, a protein that regulates cell growth and division.

  3. Rapamycin induces autophagy, a cellular cleansing process that removes old and damaged proteins.

  4. Rapamycin is a compound that has been shown to extend the lifespan of mice and restore the immune systems of elderly humans.

  5. However, whether rapamycin offers a benefit over and above lifestyle modifications known to induce autophagy, such as fasting and exercise, is untested.

  6. Some experts believe that rapamycin may be a "memetic of a healthy diet" and that eating OK and exercising may provide the same benefits as taking rapamycin.

  7. Others believe that rapamycin may offer additional benefits beyond autophagy and is a wager worth taking, given its minimal risk and cost.

MeakinMetabolicCare.com is adding rapamycin to its array of options for the Metabolic Optimization Protocol.


Stay Strong and Curious,

Charles Meakin MD, MS, MHA

Travis Christofferson MS


Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.


*Although there are no conclusive clinical trials to answer this critical question, some compelling preclinical data suggests there may be a benefit of rapamycin over and above the lifestyle modifications that inhibit mTOR. Another compound that has a significant benefit on the median lifespan in mice is a compound called acarbose. Simply put, acarbose inhibits the breakdown of complex carbohydrates into simple sugars, thus limiting absorption into the bloodstream. In this way, acarbose can be considered a form of caloric restriction – a well-established method of mTOR inhibition and lifespan enhancement in mice. Interestingly, when the ITP tested rapamycin and acarbose together, there was an additive effect over and above each drug individually in male mice.

Additionally, a 2022 study published in Nature showed that both caloric restriction and rapamycin showed benefits to delay muscle loss with age yet demonstrated very different mechanisms of action. Notably, the study showed that the combination of caloric restriction and rapamycin demonstrated an impact over each intervention alone.(5)

 

1 - Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009 Nov 24;2(98):ra75. doi: 10.1126/scisignal.2000559. PMID: 19934433; PMCID: PMC4020596.

2 - Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179. doi: 10.1126/scitranslmed.3009892. PMID: 25540326.

Image: Dossou, A.S.; Basu, A. The Emerging Roles of mTORC1 in Macromanaging Autophagy. Cancers 2019, 11, 1422. https://doi.org/10.3390/cancers11101422

3 - Ham, D.J., Börsch, A., Chojnowska, K. et al. Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle. Nat Commun 13, 2025 (2022). https://doi.org/10.1038/s41467-022-29714-6

4 - López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

5 - Kaeberlein, M., An, J. Y., Hudson, J., Green, A. S., Haddad, G., Isman, A., Nyquist, A., Zalzala, S., & Rosen, B. S. (2023). Evaluation of off-label rapamycin use to promote healthspan in 333 adults. GeroScience, 15, 7587.

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